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Pandemic and other emerging threats from animal and human influenza
Ian BarrDeputy Director
WHO Collaborating Centre for Reference and Research on Influenza
www.influenzacentre.org
The Melbourne WHO Collaborating Centrefor Reference and Research on Influenza issupported by the Australian GovernmentDepartment of Health
Where will the next pandemic influenza
virus arise from?
Influenza EcologyType A Type B
?
? ? ?
?
?
? ? ?
?
?
Type C Type D
18 subtypesWide host rangeWild water birds natural host
2 lineages“Human” virus
No subtypesLimited hostsMild disease
No subtypesLimited hosts?infect man
The influenza virus
Electron micrograph
100nm
Schematic
Note: Influenza viruses-Have a segmented genome (8 seg., 13Kb)Coding for approx. 12 proteinsNo proof-reading during replication – 1 error each new virion made
2 major surface glycoproteinsHaemagglutnin (HA), Neuraminidase (NA)
HA
NA
Influenza A is a zoonotic disease with many possible hosts
Central host are Water fowl eg. ducks, 16 Influenza A HA subtypes; most infections occur in GI tract and do not affect birds health, 2 subtypes in bats
H17/H18 in bats!
?
(Tong S. 2012, 2013)
Poultry Densities(20 billion chickens)
Swine Densities (1 billion)
Birds travel on the wing and on bike!
And pigs really DO fly!
UN Commodity Trade Statistics Database
Live swine trade routes
Slide courtesy of Martha Nelson, Fogarty Institute, NIH, USA
H5Nx HPAI
H7N9 LPAI
Avian influenza outbreaks in birds reported to FAO 2014-2016
http://empres-i.fao.org/eipws3g/#h=0 Generated by: Ahmed Al-Naqshbandi, Animal Production and Health Division-Animal Health Service, FAO
There has been no shortage of unusual influenza viruses infecting humans in recent years!
April 1 2013
H7N9
There has been no shortage of unusual influenza viruses infecting humans in recent years!
June 22 2013
H6N1
There has been no shortage of unusual influenza viruses infecting humans in recent years!
June 27 2013
H3N2v
There has been no shortage of unusual influenza viruses infecting humans in recent years!
Dec 18 2013
H10N8
There has been no shortage of unusual influenza viruses infecting humans in recent years!
Dec 30 2013
H9N2
There has been no shortage of unusual influenza viruses infecting humans in recent years!
Jan 8 2014
H5N1
There has been no shortage of unusual influenza viruses infecting humans in recent years!
May 9 2014
H5N6
There has been no shortage of unusual influenza viruses infecting humans in recent years!
May 2016
HPAI H7N9
There has been no shortage of unusual influenza viruses infecting humans in recent years!
Dec 2017
H7N4
Outcomes from these zoonotic infections
• Outcomes from H5N1 human cases
– Since 2003; 860 cases detected, 454 deaths; HFR 53%
– But in 2017; 4 cases with 2 deaths; 2018 (up to March) 0 cases
• Outcomes from H7N9 (Chinese) human cases
– Since 2013 a total of 1565 cases with 620 deaths (HFR 39%)
– 5th wave 2016-7 766 cases (incl. HPAI); 6th wave 2017-8 only 3 cases reported, ?deaths
• Outcomes from other isolated human avian influenza infections– H6N1, single case, hospitalized, recovered, no evidence of person-person transmission
– H10N8, 3 cases, 2 deaths, no evidence of transmission
– H9N2, several cases, few hospitalized, recovered, no evidence of person-person transmission
– H5N6, 17 cases (1 in 2017) – all in China, 11 deaths, no evidence of person-person transmission
• Outcomes from other isolated human swine (variant) influenza infections– In US 468 cases since 2005, small number of hospitalizations and 1 death
– Other isolated human cases in several countries eg. Switzerland 2017; mild disease
Clinical syndromes in human infections of novel subtypes of influenza A viruses
Uyeki T et al. Lancet 2017
Avian source Swine source
U.S. Human nfections withVariant swine influenza Viruses by State (since December 2005)
Reporting State
H3N2v H1N1v H1N2vTotal
Detected
Arkansas 2
Colorado 1
Delaware 1
Hawaii 1
Illinois 5 1
Indiana 154
Iowa 7 5 1
Kansas 1
Maine 2
Maryland 51
Michigan 23 1
Minnesota 9 4 6
Missouri 2
Nebraska 1
New Jersey 1
North Dakota 1
Ohio 131 3 3
Pennsylvania 17
South Dakota 1
Texas 1 1
Utah 1
West Virginia 5
Wisconsin 22 2 1
Total 434**(93%) 21 (5%) 13 (2%) 468
US Swine density 2016
OhioIndiana
Iowa
**The majority of H3N2v human cases occurred in 2012 with 309 lab confirmed cases (71% H3N2v cases); with 16 hospitalizations and 1 death
Age dependent serum antibody levels to A/Minnesota/11/2010 H3N2v of Australians by MN titre (sera sampled end 2011)
0.0
10.0
20.0
30.0
40.0
50.0
60.0
70.0
80.0
0-5yo 6-10yo 11-15yo 18-24yo 25-34yo 35-44yo 45-54yo 55-64yo >65yo
Age group
pro
po
rtio
n o
f to
tal
>40
>80
>160
>320
>640
>1280
Data generated by Karen Laurie @ WHO CC Melbourne
HI titre
Swine influenza in Australia
Virus subtype
SourceGene Segment
PB2 PB1 PA HA NP NA MP NS
H1N2* WA pigs
H3N2* WA pigs
H1N2* Qld pigs
H1N2 Qld pigs
H1N1pdm Qld pigs
H1N1pdm (post 2009 Human H1N1 (~1983-96) Human H3N2 (~1970-2003)
Apart from incidental H1N1pdm infections, Australian swine thought to be influenza free2 outbreaks detected in July/August 2012 in pigs in Western Australia and Queensland
Virus isolation and sequencing work performed with CSIRO, AAHL, Geelong
Ferret contact transmission model
❖ Infect donors intranasally
❖ 24 hr’s post infection, naïve ferret is placed in the same cage
❖ Transmission from donor to recipient ferret measured (RT-PCR + TCID50)
❖ Actually a combination between contact/aerosol transmission
Work performed by Chantal Baas
•Hurt et al, 2010 J Virol 84(18): 9427-9438
• Laurie et al, 2010 J Infect Dis 202(7):1011-1020
24 hr
+
D
R DR
Australian swine H1 & H3 viruses readily transmit & replicate in ferret contact model (C. Baas)
A(H1) viruses A(H3) viruses
Conclusion: Both the Australian H1N2v and the H3N2v were capable of close contact transmission in ferrets and probably ?humans
Can we learn from past influenza pandemics?
A(H1N1)
1918: “Spanish Flu”
40 to 50 million deaths
CFR 2-3%
Original source: ?
A(H2N2)
1957: “Asian Flu”
1 to 4 million deaths
CFR <0.2%
Original source: ?
A(H3N2)
1968: “Hong Kong Flu”
1 to 4 million deaths
CFR <0.2%
Original source: ?
A(H1N1)swl
2009: “Swine Flu”
<0.1 million deaths
CFR <0.005%
Original source: swine?
1977Re-emergence
of A(H1N1)
How did the Pandemic (H1N1) 2009 arise?No swine H1N1pdm09 virus; phylogenetic reconstruction only!
H3N2USA Triple Reassortant
USA H1N2
?Eurasian H3N2 / H1N1
H1
M, N1
PB1,2,PA,NP,NS
H1N1pdmAdapted from Smith et al. 2009
H3,N2,PB1
M,NP,NS
PB2, PA
IRAT (CDC) and TIPRA (WHO)
• IRAT (Influenza Risk Assessment Tool) for pandemic preparedness– Developed by US CDC (began 18-19 October 2011)
– CANNOT predict a future pandemic
– Intended to prioritize and maximize investments in pandemic preparedness by helping to determine which novel (new) influenza viruses to develop vaccines
– Identify key gaps in information and knowledge which can be the basis to prompt additional studies
– Document in a transparent manner the data and scientific process used to inform management decisions associated with pandemic preparedness
– Provide a flexible means to easily and regularly update the risk assessment of novel influenza viruses as new information becomes available
– Be an effective communications tool for policy makers/influenza community
– Be a measure (by using 10 scientific criteria) of the ability of an influenza virus to “emerge” as a pandemic capable virus (i.e., become capable of efficient human-to-human spread) or “impact” the human population if it did emerge
The 10 evaluation criteria of IRATProperties of the Virus
1. Genomic variation is a measure of the extent of genetic diversity or presence of known molecular signatures important for human infections and disease.
2. Receptor binding refers to the host preference (e.g., animal or human) of an influenza virus as well as the types of tissues and cells the virus is best suited to infecting (e.g., nose tissue and cells vs. deep lung tissue and cells
3. Transmission in lab animals is a measure of the ability of an influenza virus to transmit efficiently in animals in laboratory studies (transmit through the air via small infectious droplets /direct contact with an infected host)
4. Antiviral treatment susceptibility/resistance is a measure of how well an influenza virus responds to treatment with influenza antiviral drugs, such as oseltamivir, zanamivir and M2 blockers.
Attributes of the Population
5. Existing population immunity does the human population has any existing immune protection against the novel influenza virus being evaluated. Susceptibility/severity may depend on age, geographic area, or genetic factors
6. Disease severity and pathogenesis measures the severity of illness caused by a particular influenza virus in people and/or animals.
7. Antigenic relationship to vaccine candidates is a measure of how similar a novel influenza virus is when compared to a current or previously manufactured influenza vaccine strain.
Ecology and Epidemiology
8. Global distribution (animals) measures of how widespread an influenza virus is in animals. For example, is the virus found in animals in a limited area or is it found in animals from many different areas?
9. Infection in animal species refers to what kinds of animals are impacted by the influenza virus and the likelihood of human contact with these animals. For example, are influenza infections occurring in wild birds or domestic birds?
10. Human Infections are human infections with a novel influenza virus are occurring. If so, how? Eg Has human-to-human transmission or clusters of disease occurred? or how frequently/easily does transmission occur after direct/prolonged contact between humans/ infected animals?
Information on H7N4 case provided by CNIC on 15.2.2018(original H7N4 diagnosis by Jiangsu Provincial CDC)
58y female farmer from Jiangsu province, developed cough on 25/12/2017, local clinic 27/12/2017, County level hospital 30/12/2017, ICU city hospital 1/1/2018 (severe pneumonia), Discharged 22/1/2018
Next……
Influenza subject matter experts evaluate novel influenza viruses based on each of these 10 criteria “low risk” scored 1-10; 1-3; “moderate risk” scored 4-7; “high risk” scored 8-10 then elements multiplied by set weightings for BOTH “Emergence” and “Impact” then graphed.
And the output
https://www.cdc.gov/flu/pandemic-resources/monitoring/irat-virus-summaries.htm
WHO CC’s/ERL makes seed viruses against the most prevalent/concerning/different viruses currently circulating
http://www.who.int/influenza/vaccines/virus/201802_zoonotic_vaccinevirusupdate.pdf?ua=1
H7N9H5Nx
H9
H7Nx
Global interconnectivity in 21st Century – airline routes
BMJ. 2010 May 21;340:c2424. doi: 10.1136/bmj.c2424.Transmission of pandemic A/H1N1 2009 influenza on passenger aircraft: retrospective cohort study.Baker MG, Thornley CN, Mills C, Roberts S, Perera S, Peters J, Kelso A, Barr I, Wilson N.
Swine H1N1 human pandemic in 2009
Summary
• The source and subtype of the next pandemic influenza virus is unknown
• At this point in time:– H5Nx viruses are still prevalent in wild birds, less so in poultry, even less so in humans
– H7N9 viruses in man and poultry in China are vastly reduced in 2017-8 vs 2016-7
– Swine viruses (eg H1N1v, H1N2v, H3N2v) cases persist in USA (+ elsewhere) but reduced
• But……– Avian influenza viruses are still quite prevalent
– Avian surveillance (especially poultry) is heavily focused on HPAI viruses
– Influenza surveillance in swine is very limited (USA/Europe)
– Extensive reassorting of viruses occurs at all interfaces b/w av/av, sw/sw, av/sw, sw/human
– A small number of amino acid changes (HA/NA/PB2) can change transmission efficiency
• Evaluation tools, animal models and NGS give us insights into novel viruses– CDC IRAT and WHO TIPRA “rank” potential pandemic viruses by “emergence” & “severity”
– WHO has a bank of seed viruses prepared that can be rapidly used for vaccine production
– WHO has developed a series of processes for use in a pandemic eg PISA, PIRM etc.
• Need to remain flexible– May get another 2009 pandemic (mild) or a more severe pandemic (1968, moderate)
– Source wont matter once the pandemic occurs but can try to reduce current potential sources
Updated and new WHO pandemic documents
May 2017
Jan 2018
Mar 2018
Mar 2017 May 2017
